A common strategy for the intracellular delivery of membrane-impermeable molecules such as nucleic acids is the use of membrane active agents, which permeabilize membranes thus facilitating cytoplasmic delivery. Membrane active agents tend to be amphiphilic, i.e. contain both hydrophobic and hydrophilic functional groups. For the delivery of nucleic acids, membrane active agents are also cationic, which causes binding to the nucleic acid to be delivered. [unreadable] Despite to their charge density and complex stability, amphiphilic, membrane-active, cationic polymers are much less utilized than cationic lipids as DNA delivery reagents. The most well-studied, membrane-active, cationic polymers are small cationic peptides. These cationic peptides are able to interact directly with the DNA to be delivered. However, their interactions with DNA are relatively weak compared to larger polycations. This research proposal is focused on the development of cationic, membrane-active polymers that are large and charge dense enough to form stable complexes with nucleic acids. Our synthesis of membrane active polycations will be guided by the amphiphilic composition of cationic membrane active peptides, which have propensity of hydrophobic and cationic residues. [unreadable] Upon synthesis of our designed amphiphilic polymers, we will test them for the two characteristics that we believe to be key to the delivery of nucleic acids: the ability to interact with DNA, and the ability to disrupt lipid bilayers. The polymers will then be tested for their ability to deliver plasmid DNA and short interfering RNA, two nucleic acids of different size and delivery requirements. We anticipate that the transfection ability of our synthetic polymers will correlate with their membrane lytic and nucleic acid binding abilities. In addition, the determination of the relationships among transfection, lysis and binding will establish new strategies for the design of drug and gene transfer reagents. [unreadable] [unreadable]